In situ detection of lipid peroxidation and oxidative DNA damage in non-alcoholic fatty liver diseases

Seki, Shuichi; Kitada, Takuya; Sakaguchi, Hiroki; Yamada, Takehiro; Muroya, Osuke; Fujii, Hideki; Takashima, Tokuko; Kobayashi, Sho

doi:10.1016/s0168-8278(02)80938-2

Cited by 39 publications

(48 citation statements)

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“…The multiple-hit hypothesis of NASH pathogenesis suggests that lipid accumulation in hepatocytes increases liver sensitivity to a second injury or cofactor, which cooperatively induces the formation of NASH lesions (10,11). Oxidative stress has been proposed as one of these cofactors, and hepatic oxidative stress markers correlate with the severity of necroinflammation and fibrosis (31).…”

Section: Discussionmentioning

confidence: 99%

STK25 is a critical determinant in nonalcoholic steatohepatitis

Amrutkar¹,

Chursa²,

Kern

et al. 2016

FASEB j.

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Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and 10-20% of patients with NAFLD progress to nonalcoholic steatohepatitis (NASH) with a high risk of cirrhosis, liver failure, and hepatocellular carcinoma. Despite its high medical importance, the molecular mechanisms controlling progression from simple liver steatosis to NASH remain elusive. We recently identified serine/threonine protein kinase (STK)25 as a critical regulator of ectopic lipid deposition, systemic glucose, and insulin homeostasis. To elucidate the role of STK25 in the development of NASH, we challenged Stk25-knockout and transgenic mice with a methionine and choline-deficient (MCD) diet. We show that Stk25 mice are protected against MCD-diet-induced NASH, as evidenced by repressed liver steatosis, oxidative damage, inflammation, and fibrosis, whereas Stk25 transgenic mice developed a more severe NASH phenotype, compared with corresponding wild-type littermates. Consistently, NASH features were suppressed in STK25-deficient human hepatocytes cultured in MCD medium, and reciprocally enhanced in STK25-overexpressing cells. We also found a significant positive correlation in human liver biopsies between STK25 expression and NASH development. The study provides evidence for multiple roles of STK25 in NASH pathogenesis and future investigations to address the potential therapeutic relevance of pharmacological STK25 inhibitors in prevention and treatment of NASH are warranted.-Amrutkar, M., Chursa, U., Kern, M., Nuñez-Durán, E., Ståhlman, M., Sütt, S., Borén, J., Johansson, B. R., Marschall, H.-U., Blüher, M., Mahlapuu, M. STK25 is a critical determinant in nonalcoholic steatohepatitis.

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Section: Discussionmentioning

confidence: 99%

STK25 is a critical determinant in nonalcoholic steatohepatitis

Amrutkar¹,

Chursa²,

Kern

et al. 2016

FASEB j.

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“…It is this distinction that divides the appearance of a fatty liver with that of the appearance of NASH and, eventually, hepatocellular carcinoma. (7,8) Because generation of oxidative stress is one of the key mediators of this disease, the pursuit of treatments to improve the dysfunctional state of liver mitochondria has become a prime goal to alleviate the pathophysiology of NASH.…”

Section: See Editorial On Page 1074mentioning

confidence: 99%

Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice

et al. 2015

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With no approved pharmacological treatment, non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease in western countries and its worldwide prevalence continues to increase along with the growing obesity epidemic. Here we show that a high-fat high-sucrose (HFHS) diet, eliciting chronic hepatosteatosis resembling human fatty liver, lowers hepatic NAD+ levels driving reductions in hepatic mitochondrial content, function and ATP levels, in conjunction with robust increases in hepatic weight, lipid content and peroxidation in C57BL/6J mice. In an effort to assess the effect of NAD+ repletion on the development of steatosis in mice, nicotinamide riboside (NR), a precursor for NAD+ biosynthesis, was given to mice concomitant, as preventive strategy (NR-Prev), and as a therapeutic intervention (NR-Ther), to a HFHS diet. We demonstrate that NR prevents and reverts NAFLD by inducing a SIRT1- and SIRT3-dependent mitochondrial unfolded protein response (UPRmt), triggering an adaptive mitohormetic pathway to increase hepatic β-oxidation and mitochondrial complex content and activity. The cell-autonomous beneficial component of NR treatment was revealed in liver-specific Sirt1 KO mice (Sirt1hep−/−), while Apolipoprotein E-deficient (Apoe−/−) mice challenged with a high-fat high-cholesterol diet (HFC), affirmed the use of NR in other independent models of NAFLD. Conclusion: Our data warrant the future evaluation of NAD+ boosting strategies to manage the development or progression of NAFLD.

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“…DHV-1 infection is often accompanied by severe oxidative stress, which plays a vital role in the pathogenesis of hepatic injury [3,4]. The production of free radicals, such as malondialdehyde (MDA) and nitric oxide (NO), increases oxidative stress and may impair cellular functions, including nucleotide and protein synthesis, thereby contributing to the initiation and progression of hepatic injury [5,6].…”

Section: Introductionmentioning

confidence: 99%

Roles of the antioxidant properties of icariin and its phosphorylated derivative in the protection against duck virus hepatitis

et al. 2014

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BackgroundDuck viral hepatitis (DVH) is an acute disease of young ducklings with few convenient and effective veterinary drugs to treat. In pathology, present study mainly focused on the immune mechanism, but very few studies have concerned with the role of oxidative stress in the pathogenesis of DVH. To study the antioxidative and hepatoprotective effects of icariin and its phosphorylated derivative against DVH, we prepared phosphorylated icariin (p-icariin) using the sodium trimetaphosphate–sodium tripolyphosphate method. Ducklings were drunk with icariin and p-icariin after being challenged with duck hepatitis virus 1 (DHV-1). We recorded the number of dead ducklings, gross pathological changes in the liver, and changes in indices of oxidative stress and liver injury. The correlations between these indices were also analyzed.ResultsExposure to DHV-1 induced significant oxidative damage in ducklings. Administration of icariin or p-icariin attenuated liver pathological injury and significantly increased the survival rate, with better outcomes in ducklings treated with p-icariin than in those treated with icariin. Icariin and p-icariin also attenuated the changes in oxidative stress and liver injury. We found positive correlations among indices of oxidative stress (malondialdehyde and inducible nitric oxide synthase) and liver injury (alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase), suggesting that DHV-1 causes significant oxidative damage, which is related to the extent of hepatic injury.ConclusionsIcariin and p-icariin improved the survival and attenuated oxidative stress and liver dysfunction induced by DHV-1. These outcomes were better in ducklings treated with p-icariin than in those treated by icariin. The clinical effects of both components were related to their antioxidant activities.

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In situ detection of lipid peroxidation and oxidative DNA damage in non-alcoholic fatty liver diseases

Cited by 39 publications

References 0 publications

STK25 is a critical determinant in nonalcoholic steatohepatitis

STK25 is a critical determinant in nonalcoholic steatohepatitis

Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice

Roles of the antioxidant properties of icariin and its phosphorylated derivative in the protection against duck virus hepatitis

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